Novel Therapy for Huntington's Disease (HD), PI: Michael P. Vitek, Ph.D. Polyglutamine-repeat diseases, a group of at least eight disorders including Huntington's disease (HD), result from the expression of mutant proteins containing an expanded polyglutamine domain (Zoghbi and Botas 2002). The pathological-length huntingtin (Htt) protein in HD aggregates in the cytoplasm and nucleus to kill cells, particularly medium spiny neurons of the striatum (Schilling et al. 1999, Sieradzan and Mann 2001). Since not all neurons die from expression of pathological Htt proteins, the exact mechanism of death is still unclear, but several potential mechanisms have been put forward. Based on our preliminary cell culture data that were published in the Journal of Neuroscience (Colton et al. 2004), we are focused on the arginine/polyamine pathway as a key mechanism underlying the pathology of HD. Using this focus, we showed that DiFluoroMethylOrnithine (DFMO) effectively reduced a number of HD characteristics including the aggregation of pathological-length poly-glutamine Huntingtin proteins and reduced neuronal cell death resulting from expression of pathological-length poly-glutamine (poly-Q) Huntingtin proteins. With these published findings supporting the principle, this proposal seeks to define a ?Proof-of- Concept? in animals that DFMO treatment will improve several key outcomes in the progression of a Huntington's-like disease in transgenic Huntington's mice expressing a pathological length poly-Q Huntingtin protein. If we can successfully demonstrate utility of DFMO in this mouse HD model, then in future proposals, we would expand our efforts to create and test novel, patentable prodrugs of DFMO in a mouse model of HD. Since DFMO was a drug approved by the FDA for use in humans, and is currently not marketed because it is off-patent, our patent pending DFMO prodrugs would offer a more rapid regulatory path for clinical development of a novel therapy for HD patients.